Combo Delivery Flashcards
5 curative cancers
- Acute lymphocytic Leukemia (peds especially)
- some pediatric sarcomas
- germ cell tumors
- aggressive and intermediate lymphomas
- acute myeloid leukemia (in young)
Mechanisms of chemo resistance?
Altered apoptosis threshold
Drug avoidance mechanisms
Toxicity to host
Drug avoidance mechanisms
- down regulating transport mechanism
- upregulating drug efflux
- down regulating metabolic pathways
Venetoclax action
Targets Bcl-2 to restore pro-apoptotic signals
Venetoclax
mimics BH3 domain which is a natural inhibitor of the anti-apoptotic Bcl-2
How does BH3 promote apoptosis
promotes cytochrome C release from mitochondria
why is Venetoclax so special?
rare to find small molecules that mimic protein-protein interactions
Venetoclax DLT?
so potent that is causes excessive tumor lysis syndrome if not given carefully.
Antagonistic
1 + 1
Ineffective
1 + 1 = 1
Additive
1 + 1 = 2
Synergistic
1 + 1 > 2
Curative
some fractions of patients will be cured.
curative intent - cures at least 5% of people
Control
Less than 5% chance of cure, provides reasonable chance of altering natural history of disease so patients will live longer
Palliative
Alleviates symptoms or pre emptively addresses an issue that will reliably be morbid,
Textbook principles of combination chemo
- use agents with different MOA
- Use agents with non-overlapping toxicity
catch phrase for using agents of different mechanistic classes?
non-cross resistant
Bleomycin
natural, made by streptomyces. induces DNA strand breaks.
Bleomycin
little myelosuppression, doesn’t drive down WBC
Bleomycin use
lymphoma
Bleomycin warning
causes fatal pulmonary fibrosis. Risk higher in smokers and is prohibited in the presence of pulmonary hemorrhage or pulmonary embolism.
BEP stands for…
Bleomycin, Etoposide, Cisplatin
BEP uses
Germ cell tumors
RCHOP stands for…
Rituximab, Cytoxan, Doxorubicin, Vincristine, Prednisone
RCHOP uses
intermediate risk non-Hodgkin lymphoma (curative 80% of time)
ABVD stands for…
Doxorubicin, Bleomycin, Vinblastine, Dacarbazine
ABVD use
Hodgkins (90% cure)
3 + 7
Daunorubicin, Ara-C
3 + 7 use
AML
AC - T
Doxorubicin, Cyclophosphamide, Taxane
AC-T use
breast cancer
4 delivery systems
Liposomes
Targeted Liposomes
Antibody drug conjugates
Drugs with polymers
Liposomal Doxorubicin
Safer cardiac
More hand/foot syndrome
Brentuximab Vedotin
Very active drug against CD-30 expressing lymphomas (most all Hodgkin lymphomas)
Built from an antibody and a highly toxic anti-tubule drug that is way too toxic to be used in non-targeted way
Trastuzumab - Maytansine (T-DM1)
Important for Her2 expressing breast cancers
Highly toxic antitubule that is too toxic to be used in non targeted way
